Hepatitis C virus (HCV) is a member of the hepacivirus genus in the family Flaviviridae. It is the major causative agent of non-A, non-B viral hepatitis and is the major cause of transfusion-associated hepatitis and accounts for a significant proportion of hepatitis cases worldwide. Although acute HCV infection is often asymptomatic, nearly 80% of cases resolve to chronic hepatitis. The persistent property of the HCV infection has been explained by its ability to escape from the host immune surveillance through hypermutability of the exposed regions in the envelope protein E2 (Weiner, et al., Virology, 180:842-848 (1991); Weiner, et al., Proc. Natl. Acad. Sci. USA, 89:3468-3472 (1992).
Since persistent infection of HCV is related to chronic hepatitis and eventually to hepatocarcinogenesis, HCV replication is one of the targets to eliminate HCV reproduction and to prevent hepatocellular carcinoma. Unfortunately, present treatment approaches for HCV infection are characterized by relatively poor efficacy and an unfavorable side-effect profile. Therefore, intensive effort is directed at the discovery of molecules to treat this disease, including the discovery of drugs designed to inhibit HC replication, as there is a persistent need for non-peptide, small-molecule compounds that are HCV RdRp inhibitors having desirable or improved physical and chemical properties appropriate for pharmaceutical applications.
Compounds useful as inhibitors of the HCV polymerase enzyme are disclosed in U.S. patent application Ser. Nos. 10/718,337, filed Nov. 19, 2003, and 11/204,269, Aug. 15, 2005, both of which are hereby incorporated by reference in their entirety. The present invention provides improved methods and intermediate compounds useful in the preparation of compounds useful as inhibitors of the HCV polymerase enzyme.